Porous inorganic solids have found great utility as catalysts and separations media for industrial application. The openness of their microstructure allows molecules access to the relatively large surface areas of these materials that enhance their catalytic and sorptive activity. The porous materials in use today can be sorted into three broad categories using the details of their microstructure as a basis for classification. These categories are the amorphous and paracrystalline supports, the crystalline molecular sieves and modified layered materials. The detailed differences in the microstructures of these materials manifest themselves as important differences in the catalytic and sorptive behavior of the materials, as well as in differences in various observable properties used to characterize them, such as their surface area, the sizes of pores and the variability in those sizes, the presence or absence of X-ray diffraction patterns and the details in such patterns, and the appearance of the materials when their microstructure is studied by transmission electron microscopy and electron diffraction methods.
Amorphous and paracrystalline materials represent an important class of porous inorganic solids that have been used for many years in industrial applications. Typical examples of these materials are the amorphous silicas commonly used in catalyst formulations and the paracrystalline transitional aluminas used as solid acid catalysts and petroleum reforming catalyst supports. The term “amorphous” is used herein to indicate a material with no long range order, although almost all materials are crystalline to some degree, at least on the local scale. An alternate term that has been used to described these materials is “X-ray indifferent”. The microstructure of silicas consists of 10-25 nm particles of dense amorphous silica, with porosity resulting from voids between the particles. Since there is no long range order in these materials, the pore sizes tend to be distributed over a rather large range. This lack of order also manifests itself in the X-ray diffraction pattern, which is usually featureless.
Paracrystalline materials such as the transitional aluminas also have a wide distribution of pore sizes, but better defined X-ray diffraction patterns usually consisting of a few broad peaks. The microstructure of these materials consists of tiny crystalline regions of condensed alumina phases and the porosity of the materials results from irregular voids between these regions. Since, in the case of either material, there is no long range order controlling the sizes of pores in the material, the variability in pore size is typically quite high. The sizes of pores in these materials fall into a regime called the mesoporous range which is from about 1.3 nm to about 20 nm.
In sharp contrast to these structurally ill-defined solids are materials whose pore size distribution is very narrow because it is controlled by the precisely repeating crystalline nature of the materials, microstructure. These materials are called “molecular sieves”, the most important examples of which are zeolites.
Zeolites, both natural and synthetic, have been demonstrated in the past to have catalytic properties for various types of hydrocarbon conversion. Certain zeolitic materials are ordered, porous crystalline aluminosilicates having a definite crystalline structure as determined by X-ray diffraction, within which there are a large number of smaller cavities which may be interconnected by a number of still smaller channels or pores. These cavities and pores are uniform in size within a specific zeolite material. Since the dimensions of these pores are such as to accept for adsorption molecules of certain dimensions while rejecting those of larger dimensions, these materials are known as “molecular sieves” and are utilized in a variety of ways to take advantage of these properties.
Such molecular sieves, both natural and synthetic, include a wide variety of positive ion-containing crystalline silicates. These silicates can be described as a rigid three-dimensional framework of SiO4 and Periodic Table Group IIIB element oxide, e.g. AlO4, in which the tetrahedra are crosslinked by the sharing of oxygen atoms whereby the ratio of the total Group IIIB element, e.g. aluminum, and Group IVB element, e.g. silicon, atoms to oxygen atoms is 1:2.
Generally, porous substances are divided by pore size, for example, pore sizes smaller than 2 nm classified as microporous substances, between 2 and 50 nm classified as mesoporous substances and larger than 50 nm classified as macroporous substances. Of the porous substances, those having uniform channel, such as zeolite, are defined as molecular sieves and up to hundreds of types of species have been found and synthesized thus far. Zeolites play an important role as catalysts or carriers in modern chemical industries by virtue of their characteristics including selective adsorptivity, acidity and ion exchangeability. However, the molecular size of a reactant which can be utilized in catalyst conversion reactions, etc. is limited by the pore size of zeolite because zeolite is a microporous molecular sieve. For example, when ZSM-5 zeolite is applied in a catalytic cracking reaction, its reactivity becomes significantly decreased as the reactant changes from n-alkane to cycloalkane and further to branched alkane. Hence, an enormous effort has been made all over the world to synthesize molecular sieves having larger pores than that of zeolite. As a result, AlPO4, VPI-5, Cloverlite and JDF-20 having larger pore size than that of zeolites were developed. However, these molecular sieves cannot exceed the microporous limit.
Among solid substances known thus far, those having uniform channels, such as zeolites of porous crystalline aluminum silicate and of porous crystalline aluminum phosphates (AlPO4) are defined as molecular sieves, because they selectively adsorb molecules smaller than the size of the channel entrance or they allow molecules to pass through the channel. In view of crystallography, zeolite and AlPO4 are fully crystalline substances, in which atoms and channels are arranged in complete regularity. These fully crystalline molecular sieves are obtained naturally or synthesized through hydrothermal reactions. The number of fully crystalline molecular sieves obtained or synthesized thus far amount to several hundred species. They play an important role as catalysts or supports in modern chemical industries by virtue of their characteristics including selective adsorption, acidity and ion exchangeability. Examples of the current catalyst processes utilizing the characteristics of zeolite include the petroleum cracking reaction using ZSM-5 and the aromatic conversion reaction of paraffin using KL-zeolite impregnated with platinum. A significant problem of the fully crystalline molecular sieve is that it cannot be used in reactions of molecules larger than about 1.3 nm in size.
A series of mesoporous molecular sieves; including MCM-41 and MCM-48, was reported in U.S. Pat. Nos. 5,057,296 and 5,102,643. These molecular sieves show a structure in which mesopores uniform in size are arranged regularly. MCM-41, has a uniform structure exhibiting hexagonal arrangement of straight mesopores, such as honeycomb, and has a specific surface area of about 1,000 m2/g as measured by ordinary BET.
Existing molecular sieves have been produced by using inorganic or organic cations as templates, whereas those mesoporous molecular sieves are synthesized through a liquid crystal template pathway by using surfactants as templates. These mesoporous molecular sieves have the advantage that their pore sizes can be adjusted in a range of 1.6 to 10 nm by controlling the kinds of surfactants or synthetic conditions employed during the production process.
Mesoporous molecular sieves designated as SBA-1, -2 and 3 were reported in Science (1995) 268:1324. Their channels are regularly arranged, while the constituent atoms show an arrangement similar to that of amorphous silica. Mesoporous molecular sieves have regularly arranged channels larger than those of existing zeolites, thus enabling their application to adsorption, isolation or catalyst conversion reactions of relatively large molecules.
U.S. Pat. No. 6,592,764 discloses a family of high quality, hydrothermally stable and ultra large pore size mesoporous silicas by using amphiphilic block copolymers in acidic media. One member of the family, SBA-15, has a highly ordered, two-dimensional hexagonal (p6mm) honeycomb, hexagonal cage or cubic cage mesostructure. Calcination at 500° C. yields porous structures with high BET surface areas of 690 to 1,040 m2/g, and pore volumes up to 2.5 cm3/g, ultra large d(100) spacings of 7.45-45 nm, pore sizes from 4.6-50 nm and silica wall thicknesses of 3.1-6.4 nm. SBA-15 can be readily prepared over a wide range of specific pore sizes and pore wall thicknesses at low temperature (35-80° C.) using a variety of commercially available, non-toxic and biodegradable amphiphilic block copolymers, including triblock polyoxyalkylenes.
U.S. Pat. No. 6,630,170 discloses a mesoporous composition prepared from a mixture comprising hydrochloric acid, vitamin E and a silica source, wherein said vitamin E functions as a templating molecule, and said mesoporous composition exhibits uniform pore size.
U.S. Pat. No. 6,669,924 discloses a mesoporous zeolitic material having a stereoregular arrangement of uniformly-sized mesopores with diameters ranging from 2 to 50 nm and walls having a thickness of at least 4 nm and a microporous nanocrystalline structure, the mesopore walls having a stereoregular arrangement of uniformly-sized micropores with diameters less than 1.5 nm. It also discloses a method of preparing such a mesoporous zeolitic material, comprising the steps of:    a) providing a mesoporous silica having a stereoregular arrangement of uniformly-sized mesopores having diameters ranging from 2 to 50 nm and walls having a thickness of at least 4 nm and an amorphous structure;    b) impregnating said mesoporous silica with a zeolite-templating compound;    c) subjecting the impregnated mesoporous silica obtained in step (b) to a heat treatment at a temperature and for a period of time sufficient to cause transformation of said amorphous structure into a microporous nanocrystalline structure, thereby obtaining a mesoporous zeolitic material with mesopore walls having a stereoregular arrangement of uniformly-sized micropores with diameters less than 1.5 nm; and    d) removing said zeolite-templating compound from the mesoporous zeolitic material obtained in step (c).
The X-ray diffraction patterns of such material as shown in FIGS. 5, 9 and 15 of U.S. Pat. No. 6,669,924 clearly show the presence of several characteristic peaks at angles of diffraction above 3 degrees (2θ=6°). The pore distribution curves of FIG. 14 show that the more conversion is obtained in step (c), the more structural order is lost at the mesoporous level; in practice this means that reproducibility of the material may be impaired by an unaccurate control of the crystallisation time. FIG. 15 also clearly shows that structural order obtained at the mesoporous level in step (a) is lost in steps (b) and (c) when zeolitic structure appears.
Silica molecular sieves with controlled porosity crystallise from hydrogel in the presence of organic template molecules. Patterned, mesoporous silica materials with amorphous walls may be obtained using structure directing surfactants or block copolymers.
The generation of zeolite properties such as acidity and hydrothermal stability in mesostructured materials is a huge research field. The possibility to transform part of the amorphous walls of a mesoporous precursor into zeolite framework was already demonstrated, but segregation of a zeolite phase from the mesostructure as conversion proceeds seems difficult to avoid, as evidenced by U.S. Pat. No. 6,669,924.
There is a need in the art for producing mesoporous oxide based material with high heat stability and improved hydro-thermal stability and with improved reproducibility over existing materials.
Another difficult problem for the pharmaceutical industry is the formulation of drugs having low or very low water-solubility into solid dosage forms, especially formulations intended for immediate release. Few solutions to this problem have been disclosed in the art. For instance, U.S. Patent Publication No. 2001/0048946 provides solid dosage forms of sparingly water-soluble pharmaceutical agents, i.e. solid or crystalline drugs having a water-solubility of 10 to 33 μg/ml at 25° C., such as glitazones. More particularly, this document discloses a pharmaceutical composition in the form of a solid particulate dispersion of such a pharmaceutical agent dispersed throughout a matrix of a water-soluble polymer such as polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose. In a preferred embodiment, the particulate pharmaceutical agent is dispersed in the water-soluble polymer in a weight ratio of about 10% to about 90% active ingredient to about 90% to about 10% polymer. Other conventional excipients such as glycerin, propyleneglycol, Tween, stearic acid salts and the like can be added.
U.S. Patent Publication No. 2001/0044409 discloses a process for the preparation of a poorly water soluble drug in solid dispersion comprising the steps of (a) blending the drug with a carrier, (b) dissolving a surfactant and a plasticizer/solubilizer in water, (c) spraying the surfactant-plasticizer/solubilizer solution onto the drug/carrier mixture in a fluid bed granulator, (d) extruding the resulting granulation through a twin screw extruder with at least one heating zone, and (e) milling the extrudate to a powdery mass of the solid drug dispersion. Within this process, the carrier may be selected from the group consisting of polyvinylpyrrolidone, high molecular weight polyethylene glycol, urea, citric acid, vinyl acetate copolymer, acrylic polymers, succinic acid, sugars and mixtures thereof; the plasticizer/solubilizer may be selected from the group consisting of low molecular weight polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures thereof, and the said surfactant may be selected from the group consisting of Tween, Span, Pluronics, polyoxyethylene sorbitol esters, monodiglycerides, polyoxyethylene acid polyoxyethylene alcohol and mixtures thereof. This process suffers from the disadvantage of providing a heating zone in the twin screw extruder and consequently controlling and monitoring the temperature profile of the extruder.
However, none of the above processes appear to be successful in formulating solid dosage forms of drugs having very low water-solubility, i.e. a solubility lower than 10 μg/ml, preferably lower than 5 μg/ml. This problem is applicable to a large number of drugs, including those belonging to the family of diaminopyrimidines, such as stated in U.S. Pat. No. 6,211,185.
U.S. Pat. No. 3,639,637 discloses oestrogen compositions for the preparation of stable aqueous suspensions that can be sprayed onto animal feed, comprising (by weight) 70-95% of water-dispersible gel-forming microcrystalline cellulose and 5-30% of finely-divided diethylstilbestrol (a compound which is virtually insoluble in water) and optionally further up to one third of the weight of the composition of a hydrocolloid selected from the group consisting of sodium carboxy-methylcellulose, methylcellulose and hydroxyethylcellulose. The two latter cellulose compounds are known, namely from EP-A-403,383, to contribute to an extended linear drug release rate.
WO-A-99/12524 solves the problem of drug formulations with both a relatively fast or quick onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time, by providing an oral modified release multiple-units composition wherein the unit dosage form comprises at least (i) a first fraction being able to release at least 50% of the drug within the first 20 minutes of a certain dissolution method, and (ii) a second fraction for delayed and extended release of the drug. The multiple-units of the first fraction may be granulates or, provided that a surfactant is added to the formulation, coated or uncoated pellets. Formulation of the first fraction depends on the specific drug but typically includes wet-granulation, and an antacid-like or other alkaline substance was found to have a pronounced increasing effect on the release rate.
U.S. Pat. No. 5,646,131 discloses (example 4) rapidly dissolving capsules containing a granulate formulation of a water-insoluble or sparingly soluble drug, such as terfenadine (less than 0.01 mg/ml water-solubility), surfactants (Tween 80 and sodium lauryl sulfate), cyclodextrin, Avicel PH 101 (microcrystalline cellulose) and a disintegrant/swelling agent (Primojel®, i.e. sodium carboxymethyl starch) in a weight ratio of 10:72 to Avicel. These capsules provide better drug absorption, due to the presence of cyclodextrin, as evidenced by the figure showing a 90% drug release within 45 minutes.
U.S. Pat. No. 4,235,892 discloses a series of 1-aryl-2-acylamido-3-fluoro-1-propanol antibacterial agents including D-(threo)-1-p-methylsulfonyl phenyl-2-dichloroacetamido-3-fluoro-1-propanol, an antibacterial agent known as florfenicol and useful for veterinary purposes. Florfenicol has low solubility in water (about 1.3 mg/ml), as well as in many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin, and benzyl alcohol. For oral administration, these 1-aryl-2-acylamido-3-fluoro-1-propanol may be compounded in the form of tablets, or may even be admixed with animal feed. U.S. Pat. No. 4,235,892 therefore discloses making tablets by compressing granules of a composition comprising the said 1-aryl-2-acylamido-3-fluoro-1-propanol (in a drug loading range from 8.3% to 41.7% by weight), lactose, microcrystalline cellulose, starch and magnesium stearate.
The Biopharmaceutical Classification System (hereinafter referred as BCS) according to G. Amidon et al. in Pharm. Res. (1995) 12:413-420 provides for two classes of poorly soluble drugs, i.e. Class II and Class IV, and a class of highly soluble drugs, i.e. Class I. According to M. Martinez et al., Applying the Biopharmaceutical Classification System to Veterinary Pharmaceutical Products (Part I: Biopharmaceutics and Formulation Consideration) in Advanced Drug Delivery Reviews (2002) 54:805-824, a drug substance should be classified as highly soluble when the highest dose strength is soluble in at most 250 ml of aqueous media over the pH range 1-7.5. In view of its water solubility (1.3 mg/ml) and of a maximal dose of 20 mg/kg for pigs, it is easy to calculate that the highest dose strength of florfenicol administered to pigs is soluble in an amount of water which is well above the limit value for the definition of a class I BCS highly soluble drug. Furthermore it is known from J. Voorspoels et al. in The Veterinary Record (October 1999) that florfenicol has a good oral bioavailability, so that it can be classified as a Class II compound as it is not a highly soluble drug and it shows no absorption problems.
There is a specific need in the art to provide a solid formulation of drugs with a water-solubility like florfenicol or lower. Florfenicol is a drug for oral administration to warm-blooded animals, such as cattle with naturally-occurring bovine respiratory disease, swine, sheep, goats and poultry, which at present is only available in the form of injectable solutions. Until now the skilled person has failed in the design of such a solid formulation of florfenicol, which can further be admixed with animal feed if necessary. Also there is a need for a solid formulation for low solubility drugs for human therapies.
Similar problems, yet unsolved in a suitable manner, arise with a growing number of therapeutic drugs with poor solubility like for instance itraconazole and diazepam. Solving such problems constitutes another goal of the present invention.